Close to 1.7 billion people worldwide are asymptomatically infected with Mycobacterium tuberculosis (Mtb), the etiological agent of TB. Furthermore, co-infection with HIV dramatically increases the risk of developing active TB, and constitutes a major impediment to worldwide public health control measures. The only available vaccine, M. bovis BCG, is insufficient at protecting all age groups against the most common presentation of the disease, pulmonary TB. While it is widely recognized that cellular metabolism plays a fundamental role in orchestrating protective (and destructive) immune responses, a significant gap in our knowledge is how Mtb dysregulates host immunometabolism to establish a persistent infection. Our long-term goal is to better understand the mechanisms by which HIV modulates TB latency and how these mechanisms can be manipulated for therapeutic and prophylactic purposes. The objective of this work is to generate a mechanistic understanding of the role of immunometabolism in Mtb and HIV infection. Our central hypothesis is that metabolic reprogramming during Mtb/HIV coinfection drives a dysregulated immune response that promotes lethal pathology in susceptible hosts. This hypothesis has been formulated on the basis of our strong preliminary data derived from novel stable isotope (C13-glucose) incorporation assays using freshly resected human tuberculous lung tissue (?Warburg slices?), which show that Mtb causes a shift in host cell energy metabolism. Secondly, we will apply novel techniques such as real-time metabolic flux analysis to non- invasively measure the oxygen consumption rate, extracellular acidification rate, spare respiratory capacity, maximal respiration, and ATP turnover of cells infected with Mtb and/or HIV. This powerful technology has not yet been applied to study the bioenergetics of bacterial/viral host interaction. Thirdly, this technology has enabled us to demonstrate that the bioenergetic capacity of monocytes isolated from PBMCs in TB patients is dramatically impaired compared to that of healthy volunteers. The rationale is that successful completion of this proposal will (i) establish a new, clinically relevant paradigm of TB/HIV disease that sheds light on dysregulated host immune responses during pathogenesis. This will advance development of new diagnostic tools and host-directed therapies that target metabolism in infected individuals. Secondly, (ii) this proposal will provide a unique diagnostic/prognostic platform to compare a well-established vaccine strain with pathogenic Mtb, which may also provide new parameters to test future vaccine strains and predict candidates that will elicit robust protective immune responses upon Mtb challenge. The research is innovative, in our opinion, because it represents a new and substantive departure from the status quo by applying novel technologies and unique patient cohorts to examine immunometabolism as paradigm to better understand TB/HIV disease. This contribution is significant because it is the first step in the continuum of TB/HIV research that has the potential to make a lasting, positive change to existing paradigms in HIV/TB research.